OP0193 EFFICACY AND SAFETY OF EMAPALUMAB, AN ANTI-INTERFERON GAMMA MONOCLONAL ANTIBODY, IN PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME (MAS) IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (sJIA) WHO HAD FAILED HIGH-DOSE GLUCOCORTICOIDS
Authors: F. De Benedetti, A. Grom, P. Brogan, C. Bracaglia, M. Pardeo, G. Marucci, D. Eleftheriou, C. Papadopoulou, P. Quartier, J. Anton, R. Frederiksen, V. Asnaghi, C. de Min
Journal: Annals of the Rheumatic Diseases (2022)

Background MAS is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients with sJIA. The mainstay of treatment for MAS is high dose glucocorticoids (GCs); however, GCs do not provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and mortality remain high. Data from animal models of MAS and from observational studies in patients suggest that overproduction of IFNγ is a driver of the hyperinflammation observed in MAS; neutralization of IFNγ has been shown to revert the signs and symptoms of MAS in murine models, and high IFNγ levels are strongly correlated with laboratory parameters of disease severity in patients. Objectives To assess the efficacy and safety of intravenous (IV) infusions of emapalumab, a fully human, anti-IFNγ monoclonal antibody, in patients with MAS in sJIA. Methods Open-label, single-arm, phase 2 study ( NCT03311854 ) that included patients with MAS (2016 ACR/EULAR criteria) in sJIA who had failed high-dose IV GCs and other treatments. Emapalumab was initiated at a dose of 6 mg/kg on Day 0 and continued at 3 mg/kg every 3 days until Day 15, and then twice weekly until Day 28 to ensure rapid and complete IFNγ neutralization after initiating treatment. As per protocol, 10 infusions were planned over the 4 weeks; however, treatment could be shortened if MAS remission was achieved earlier, or extended if required to achieve remission. Complete response (CR) was defined as resolution of clinical signs and symptoms of MAS according to the investigator, and normalization of laboratory parameters relevant to MAS. All patients were followed up for 4 weeks after the last infusion of emapalumab and offered to enter a 1-year, follow-up study ( NCT02069899 ). Results Fourteen patients (10 females) were enrolled (11 in Europe, 3 in the USA). Several patients had previously received cyclosporine A and/or anakinra, in addition to high-dose GCs. Six patients received emapalumab until Day 28. Seven patients discontinued emapalumab early due to MAS remission (as per investigator’s assessment); one patient received treatment up to Day 38. Emapalumab treatment rapidly neutralized IFNγ, as documented by CXCL9 levels. A CR was achieved by 13/14 patients during the study. One patient stopped emapalumab after 3 doses because of achievement of MAS remission as per investigator’s assessment, but lactate dehydrogenase levels remained &gt;1.5× upper limit of normal. At Week 8, 11/14 patients had a CR; 2 achieved a CR during the study, but not at Week 8, because of a single laboratory parameter abnormality in each patient. Overall, all measured laboratory parameters related to MAS activity rapidly improved with emapalumab treatment. GCs were tapered in all patients by Week 8 (≥50% reduction, n=12; GC dose ≤1 mg/kg/day, n=8). Administration of anakinra for the treatment of underlying sJIA was maintained/introduced during the study, as required. No patients discontinued treatment for safety reasons. One treatment-related serious adverse event was reported (cytomegalovirus reactivation that resolved with antiviral treatment). All patients entered the long-term, follow-up study and were alive at last visit. Conclusion Emapalumab administration led to rapid IFNγ neutralization, was efficacious in controlling MAS in all patients, and was well tolerated with a favorable safety profile. These results support the pathogenic role of IFNγ in MAS in sJIA and the therapeutic value of IFNγ neutralization in MAS patients who have failed high-dose GCs. Disclosure of Interests Fabrizio De Benedetti Consultant of: Sobi, AbbVie, Pfizer, Roche, Sanofi, Novartis, Novimmune, Grant/research support from: Sobi, AbbVie, Pfizer, Roche, Sanofi, Novartis, Novimmune, Alexei Grom Consultant of: Novartis, AB2 Bio, Paul Brogan Consultant of: Sobi, Novartis, Roche, UCB, Claudia Bracaglia: None declared, Manuela Pardeo: None declared, Giulia Marucci: None declared, Despina Eleftheriou Speakers bureau: Sobi, Charalampia Papadopoulou Speakers bureau: Sobi, Pierre Quartier Speakers bureau: Sobi, AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Consultant of: Sobi, AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Jordi Anton Consultant of: Sobi, Novartis, Roche, Pfizer, AbbVie, GSK, Rikke Frederiksen Employee of: Sobi, Veronica Asnaghi Employee of: Sobi, Cristina de Min Consultant of: Sobi